Page 28 - H. Cell signaling
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[H. Cell signaling-21]
CXXC5, a target for the longitudinal bone growth, regulates
growth plate senescence
Sehee Choi¹, Dasung Lee¹, Eunhwan Kim¹, Minguen Yoon¹, Yeong Chan Ryu¹, Kang-Yell Choi¹
¹Biotechnology, Yonsei University, Seoul 03722, South Korea
Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms
of this phenomenon are largely unexplored. Here, we examined Wnt responsive genes before and after growth
plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway,
was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate.
Cxxc5-/- mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by
interacting with dishevelled (DVL),we sought to identify small molecules capable of disrupting this interaction. In
vitro screening assay monitoring CXXC5-DVL interaction revealed that several indirubin analogs were effective
antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through
delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal
an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate activity.
